Deuterium-enriched bupropion

ABSTRACT

The present application describes deuterium-enriched bupropion, pharmaceutically acceptable salt forms thereof, and methods of treating using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/196,231, filed 21 Aug. 2008 now abandoned, which claims the benefitof and priority to U.S. Provisional Patent Application Ser. No.60/972,205, filed 13 Sep. 2007 , the disclosure of which is incorporatedherein by reference.

FIELD OF THE INVENTION

This invention relates generally to deuterium-enriched bupropion,pharmaceutical compositions containing the same, and methods of usingthe same.

BACKGROUND OF THE INVENTION

Bupropion, shown below, is a well known norepinephrine reuptakeinhibitor and dopamine reuptake inhibitor.

Since bupropion is a known and useful pharmaceutical, it is desirable todiscover novel derivatives thereof. Bupropion is described in U.S. Pat.No. 3,819,706; the contents of which are incorporated herein byreference.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to providedeuterium-enriched bupropion or a pharmaceutically acceptable saltthereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of thedeuterium-enriched compounds of the present invention or apharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method fortreating a disease selected from antidepressant and/or as a smokingcessation aid, comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thedeuterium-enriched compounds of the present invention or apharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a noveldeuterium-enriched bupropion or a pharmaceutically acceptable saltthereof for use in therapy.

It is another object of the present invention to provide the use of anovel deuterium-enriched bupropion or a pharmaceutically acceptable saltthereof for the manufacture of a medicament (e.g., for the treatment ofantidepressant and/or as a smoking cessation aid).

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventor's discovery ofthe presently claimed deuterium-enriched bupropion.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen andhas an atomic weight of 2.0144. Hydrogen naturally occurs as a mixtureof the isotopes ¹H (hydrogen or protium), D (²H or deuterium), and T (³Hor tritium). The natural abundance of deuterium is 0.015%. One ofordinary skill in the art recognizes that in all chemical compounds witha H atom, the H atom actually represents a mixture of H and D, withabout 0.015% being D. Thus, compounds with a level of deuterium that hasbeen enriched to be greater than its natural abundance of 0.015%, shouldbe considered unnatural and, as a result, novel over their non-enrichedcounterparts.

All percentages given for the amount of deuterium present are molepercentages.

It can be quite difficult in the laboratory to achieve 100% deuterationat any one site of a lab scale amount of compound (e.g., milligram orgreater). When 100% deuteration is recited or a deuterium atom isspecifically shown in a structure, it is assumed that a small percentageof hydrogen may still be present. Deuterium-enriched can be achieved byeither exchanging protons with deuterium or by synthesizing the moleculewith enriched starting materials.

The present invention provides deuterium-enriched bupropion or apharmaceutically acceptable salt thereof. There are eighteen hydrogenatoms in the bupropion portion of bupropion as show by variables R₁-R₁₈in formula I below.

The hydrogens present on bupropion have different capacities forexchange with deuterium. Hydrogen atom R₁ is easily exchangeable underphysiological conditions and, if replaced by a deuterium atom, it isexpected that it will readily exchange for a proton after administrationto a patient. Hydrogen atom R₂ may be exchanged for a deuterium atom viathe action of a base such as EtOD/EtOH. The remaining hydrogen atoms arenot easily exchangeable for deuterium atoms. However, deuterium atoms atthe remaining positions may be incorporated by the use of deuteratedstarting materials or intermediates during the construction ofbupropion.

The present invention is based on increasing the amount of deuteriumpresent in bupropion above its natural abundance. This increasing iscalled enrichment or deuterium-enrichment. If not specifically noted,the percentage of enrichment refers to the percentage of deuteriumpresent in the compound, mixture of compounds, or composition. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %. Since there are 18 hydrogensin bupropion, replacement of a single hydrogen atom with deuterium wouldresult in a molecule with about 6% deuterium enrichment. In order toachieve enrichment less than about 6%, but above the natural abundance,only partial deuteration of one site is required. Thus, less than about6% enrichment would still refer to deuterium-enriched bupropion.

With the natural abundance of deuterium being 0.015%, one would expectthat for approximately every 6,667 molecules of bupropion(1/0.00015=6,667), there is one naturally occurring molecule with onedeuterium present. Since bupropion has 18 positions, one would roughlyexpect that for approximately every 120,006 molecules of bupropion(18×6,667), all 18 different, naturally occurring, mono-deuteratedbupropions would be present. This approximation is a rough estimate asit doesn't take into account the different exchange rates of thehydrogen atoms on bupropion. For naturally occurring molecules with morethan one deuterium, the numbers become vastly larger. In view of thisnatural abundance, the present invention, in an embodiment, relates toan amount of an deuterium enriched compound, whereby the enrichmentrecited will be more than naturally occurring deuterated molecules.

In view of the natural abundance of deuterium-enriched bupropion, thepresent invention also relates to isolated or purifieddeuterium-enriched bupropion. The isolated or purifieddeuterium-enriched bupropion is a group of molecules whose deuteriumlevels are above the naturally occurring levels (e.g., 6%). The isolatedor purified deuterium-enriched bupropion can be obtained by techniquesknown to those of skill in the art (e.g., see the syntheses describedbelow).

The present invention also relates to compositions comprisingdeuterium-enriched bupropion. The compositions require the presence ofdeuterium-enriched bupropion which is greater than its naturalabundance. For example, the compositions of the present invention cancomprise (a) a μg of a deuterium-enriched bupropion; (b) a mg of adeuterium-enriched bupropion; and, (c) a gram of a deuterium-enrichedbupropion.

In an embodiment, the present invention provides an amount of a noveldeuterium-enriched bupropion.

Examples of amounts include, but are not limited to (a) at least 0.01,0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, to 1 mole, (b) at least0.1 moles, and (c) at least 1 mole of the compound. The present amountsalso cover lab-scale (e.g., gram scale), kilo-lab scale (e.g., kilogramscale), and industrial or commercial scale (e.g., multi-kilogram orabove scale) quantities as these will be more useful in the actualmanufacture of a pharmaceutical. Industrial/commercial scale refers tothe amount of product that would be produced in a batch that wasdesigned for clinical testing, formulation, sale/distribution to thepublic, etc.

In another embodiment, the present invention provides a novel, deuteriumenriched compound of formula I or a pharmaceutically acceptable saltthereof.

wherein R₁-R₁₈ are independently selected from H and D; and theabundance of deuterium in R₁-R₁₈ is at least 6%. The abundance can alsobe (a) at least 11%, (b) at least 17%, (c) at least 22%, (d) at least28%, (e) at least 33%, (f) at least 39%, (g) at least 44%, (h) at least50%, (i) at least 56%, (j) at least 61%, (k) at least 67%, (l) at least72%, (m) at least 78%, (n) at least 83%, (o) at least 89%, (p) at least94%, and (q) 100%.

In another embodiment, the present invention provides a novel, deuteriumenriched compound of formula I or a pharmaceutically acceptable saltthereof, wherein the abundance of deuterium in R₁ is 100%.

In another embodiment, the present invention provides a novel, deuteriumenriched compound of formula I or a pharmaceutically acceptable saltthereof, wherein the abundance of deuterium in R₂ is 100%.

In another embodiment, the present invention provides a novel, deuteriumenriched compound of formula I or a pharmaceutically acceptable saltthereof, wherein the abundance of deuterium in R₃-R₅ is at least 33%.The abundance can also be (a) at least 67%, and (b) 100%.

In another embodiment, the present invention provides a novel, deuteriumenriched compound of formula I, wherein the abundance of deuterium inR₆-R₉ is at least 25%. The abundance can also be (a) at least 50%, (b)at least 75%, and (c) 100%.

In another embodiment, the present invention provides a novel, deuteriumenriched compound of formula I or a pharmaceutically acceptable saltthereof, wherein the abundance of deuterium in R₁₀-R₁₈ is at least 11%.The abundance can also be (a) at least 22%, (b) at least 33%, (c) atleast 44%, (d) at least 56%, (e) at least 67%, (f) at least 78%, (g) atleast 89%, and (h) 100%.

In another embodiment, the present invention provides an isolated novel,deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof.

wherein R₁-R₁₈ are independently selected from H and D; and theabundance of deuterium in R₁-R₁₈ is at least 6%. The abundance can alsobe (a) at least 11%, (b) at least 17%, (c) at least 22%, (d) at least28%, (e) at least 33%, (f) at least 39%, (g) at least 44%, (h) at least50%, (i) at least 56%, (j) at least 61%, (k) at least 67%, (l) at least72%, (m) at least 78%, (n) at least 83%, (o) at least 89%, (p) at least94%, and (q) 100%.

In another embodiment, the present invention provides an isolated novel,deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₁ is100%.

In another embodiment, the present invention provides an isolated novel,deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₂ is100%.

In another embodiment, the present invention provides an isolated novel,deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₃-R₅ isat least 33%. The abundance can also be (a) at least 67%, and (b) 100%.

In another embodiment, the present invention provides an isolated novel,deuterium enriched compound of formula I, wherein the abundance ofdeuterium in R₆-R₉ is at least 25%. The abundance can also be (a) atleast 50%, (b) at least 75%, and (c) 100%.

In another embodiment, the present invention provides an isolated novel,deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₁₀-R₁₈is at least 11%. The abundance can also be (a) at least 22%, (b) atleast 33%, (c) at least 44%, (d) at least 56%, (e) at least 67%, (f) atleast 78%, (g) at least 89%, and (h) 100%.

In another embodiment, the present invention provides novel mixture ofdeuterium enriched compounds of formula I or a pharmaceuticallyacceptable salt thereof

wherein R₁-R₁₈ are independently selected from H and D; and theabundance of deuterium in R₁-R₁₈ is at least 6%. The abundance can alsobe (a) at least 11%, (b) at least 17%, (c) at least 22%, (d) at least28%, (e) at least 33%, (f) at least 39%, (g) at least 44%, (h) at least50%, (i) at least 56%, (j) at least 61%, (k) at least 67%, (l) at least72%, (m) at least 78%, (n) at least 83%, (o) at least 89%, (p) at least94%, and (q) 100%.

In another embodiment, the present invention provides a novel mixtureof, deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₁ is100%.

In another embodiment, the present invention provides a novel mixtureof, deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₂ is100%.

In another embodiment, the present invention provides a novel mixtureof, deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₃-R₅ isat least 33%. The abundance can also be (a) at least 67%, and (b) 100%.

In another embodiment, the present invention provides a novel mixtureof, deuterium enriched compound of formula I, wherein the abundance ofdeuterium in R₆-R₉ is at least 25%. The abundance can also be (a) atleast 50%, (b) at least 75%, and (c) 100%.

In another embodiment, the present invention provides a novel mixtureof, deuterium enriched compound of formula I or a pharmaceuticallyacceptable salt thereof, wherein the abundance of deuterium in R₁₀-R₁₈is at least 11%. The abundance can also be (a) at least 22%, (b) atleast 33%, (c) at least 44%, (d) at least 56%, (e) at least 67%, (f) atleast 78%, (g) at least 89%, and (h) 100%.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a deuterium-enrichedcompound of the present invention.

In another embodiment, the present invention provides a novel method fortreating a disease selected from antidepressant and/or as a smokingcessation aid comprising: administering to a patient in need thereof atherapeutically effective amount of a deuterium-enriched compound of thepresent invention.

In another embodiment, the present invention provides an amount of adeuterium-enriched compound of the present invention as described abovefor use in therapy.

In another embodiment, the present invention provides the use of anamount of a deuterium-enriched compound of the present invention for themanufacture of a medicament (e.g., for the treatment of antidepressantand/or as a smoking cessation aid).

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is intended to be taken individually as itsown independent preferred embodiment. Furthermore, any element of anembodiment is meant to be combined with any and all other elements fromany embodiment to describe an additional embodiment.

DEFINITIONS

The examples provided in the definitions present in this application arenon-inclusive unless otherwise stated. They include but are not limitedto the recited examples.

The compounds of the present invention may have asymmetric centers.Compounds of the present invention containing an asymmetricallysubstituted atom may be isolated in optically active or racemic forms.It is well known in the art how to prepare optically active forms, suchas by resolution of racemic forms or by synthesis from optically activestarting materials. All processes used to prepare compounds of thepresent invention and intermediates made therein are considered to bepart of the present invention. All tautomers of shown or describedcompounds are also considered to be part of the present invention.

“Host” preferably refers to a human. It also includes other mammalsincluding the equine, porcine, bovine, feline, and canine families.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, e.g., arresting it development; and/or (c)relieving the disease-state, e.g., causing regression of the diseasestate until a desired endpoint is reached. Treating also includes theamelioration of a symptom of a disease (e.g., lessen the pain ordiscomfort), wherein such amelioration may or may not be directlyaffecting the disease (e.g., cause, transmission, expression, etc.).

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to treat the desired condition or disorder. “Therapeuticallyeffective amount” includes an amount of the combination of compoundsclaimed that is effective to treat the desired condition or disorder.The combination of compounds is preferably a synergistic combination.Synergy, as described, for example, by Chou and Talalay, Adv. EnzymeRegul. 1984, 22:27-55, occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at sub-optimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased antiviral effect, or some other beneficialeffect of the combination compared with the individual components.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofthe basic residues. The pharmaceutically acceptable salts include theconventional quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

Synthesis

Scheme 1 shows an example of how to prepare bupropion.

Using combinations of various deuterated starting materials andintermediates shown in Scheme 1, a person skilled in the art of organicchemistry should be able to prepare a wide variety of deuteratedbupropion analogs.

Examples

Table 1 provides compounds that are representative examples of thepresent invention. When one of R₁-R₁₈ is present, it is selected from Hor D.

1

2

3

4

5

6

Table 2 provides compounds that are representative examples of thepresent invention. Where H is shown, it represents naturally abundanthydrogen.

7

8

9

10

11

12

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

What is claimed is:
 1. A deuterium-enriched compound of formula I or apharmaceutically acceptable salt thereof:

wherein R₁ and R₃-R₁₈ are independently selected from H and D.
 2. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt form thereof.
 3. A method fortreating a disease selected from depression and smoking, comprising:administering, to a patient in need thereof, a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltform thereof.
 4. A compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt form thereof.
 5. A compound ofclaim 1, wherein the compound is:

or a pharmaceutically acceptable salt form thereof.
 6. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 4 or apharmaceutically acceptable salt form thereof.
 7. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 5 or apharmaceutically acceptable salt form thereof.
 8. A method for treatinga disease selected from depression and smoking, comprising:administering, to a patient in need thereof, a therapeutically effectiveamount of a compound of claim 4 or a pharmaceutically acceptable saltform thereof.
 9. A method for treating a disease selected fromdepression and smoking, comprising: administering, to a patient in needthereof, a therapeutically effective amount of a compound of claim 5 ora pharmaceutically acceptable salt form thereof.